Latest Review Date: May 2024

Category: Laboratory

POLICY:

The use of FFN (Fetal Fibronectin Enzyme) assays may be considered medically necessary for use in women:

• with singleton or twin gestations; and
• with intact amniotic membranes; and
• cervical dilation less than 3 cm; and
• who are experiencing symptoms suggestive of preterm labor between 24 and less than 35 weeks gestation.

*This population represents women who are most likely to be hospitalized and treated in an attempt to prevent preterm birth.

All other applications of the FFN (Fetal Fibronectin Enzyme) assay are considered investigational, including, but not limited to, the following:

• As part of routine pregnancy monitoring in asymptomatic women with singleton gestation and no risk factors for preterm birth;
• As part of clinical monitoring of asymptomatic women at high risk for preterm birth, including, but not limited to:
  • those with multiple gestations;
  • history of preterm birth;
  • uterine malformation;
  • cervical incompetence;
  • history of two or more spontaneous second trimester abortions;
• As part of clinical monitoring in women with:
  • triplet or higher-order gestations;  
  • intact amniotic membranes;
  • cervical dilation less than 3 cm;
  • who are experiencing symptoms suggestive of preterm labor;
• As a test to identify women at term being considered for induction that are likely to deliver within 24-48 hours and therefore, do not require induction.

DESCRIPTION OF PROCEDURE OR SERVICE:

Assessment of fetal fibronectin (FFN) is proposed for use in the diagnosis and management of preterm labor (PTL) and in the management of women at term being considered for induction. A rapid test is available that can provide results within 20 minutes. FFN testing has been considered for several categories of patients including women who are experiencing symptoms of preterm labor, asymptomatic women at increased risk of pre-term labor and asymptomatic women as part of routine pregnancy care.

Fetal Fibronectin (FFN) is a high-molecular-weight glycoprotein that can be isolated from fetal connective tissue, placenta, and amniotic fluid. Fetal fibronectin can be measured in cervicovaginal secretions early in pregnancy (normally found in cervical secretion until 16-20 weeks of gestation) and at term, but is rarely detectable between 21 and 37 weeks’ gestation in normal pregnancies that are delivered at term. However, in several studies FFN may also be detected between 21 and 37 weeks in association with preterm delivery. It has been hypothesized that elevation of FFN signals the separation of the placental uterine junction, and thus FFN may be a useful marker in predicting which women will achieve spontaneous labor within a short period of time. Originally, immunoassays of FFN were available only at specialized reference laboratories performing the enzyme linked immunoabsorbent assay (ELISA), which produced semi-quantitative results. Because tests had to be sent to a reference lab, there was a minimum 24-hour delay between sampling and receipt of the results. A rapid fetal fibronectin test is now available permitting results within 20 minutes of testing. This assay produces qualitative results, reported as positive, negative, or indeterminate. Generally, a FFN level of 50 ng/mL or higher is considered a positive test.

The clinical importance of measurements of FFN relates to the diagnosis and management of preterm labor. Clinical symptoms of PTL are nonspecific and include vaginal spotting or bleeding, increased or changed vaginal discharge, intermittent abdominal cramping, backache, and inappropriate uterine contractions. Signs of PTL include cervical effacement and dilation, or a shortened cervix, as assessed by transvaginal ultrasound. When symptoms of PTL develop and the physical exam does not immediately confirm a diagnosis of progressive PTL, the patient is usually hospitalized for an initial period of observation to determine if the symptoms subside or progress. During this time, bed rest and possible treatment in the form of IV hydration, antibiotics, tocolytic drugs, or prostaglandin inhibitors depending upon the symptoms and results of the physical exam, are prescribed. All current tocolytic agents are considered superior to no treatment at delaying delivery for both 48 hours and seven days, however, prostaglandin inhibitors are considered superior to the other agents and may be considered the optimal first-line agent before 32 weeks of gestation to delay delivery. In many cases, the symptoms of PTL subside during the period of observation and prophylactic treatment. However, if the signs and symptoms of PTL are sufficiently advanced or suspicious, delivery within seven days may be highly likely. In these cases, particularly if gestation is 34 weeks or less, corticosteroid treatment for the induction of fetal lung maturity is indicated.

Accurate diagnosis of PTL is extremely difficult; current methods of assessing risk can result in overdiagnoses of PTL. FFN has been investigated as a method to more accurately diagnose PTL and thus eliminate unnecessary hospitalizations, tocolytic therapy, and corticosteroid treatment in women who do not truly have PTL. The use of FFN has been studied in several different categories of patients:

• Women of average risk who are experiencing symptoms suggestive of preterm labor;
• Women with multiple gestations or other high-risk factors for preterm birth who are experiencing symptoms of preterm labor;
• Asymptomatic women with no risk factors for preterm birth; FFN is used in these patients as a screening test at certain intervals during pregnancy;
• Asymptomatic women with multiple gestations or other high-risk characteristics of preterm birth;
• Women at term being considered for induction who are likely to deliver within 24-48 hours and therefore do not require induction.

KEY POINTS:

Policy was updated with literature review performed on May 1, 2024.

Summary of Evidence

Systematic reviews have found a significant impact of FFN testing in women with singleton pregnancies and symptoms of preterm labor on reduced rates of preterm birth before 37 weeks’ gestation and on hospitalization rates. There is insufficient evidence that FFN testing improves the net health outcome for asymptomatic women at average risk or at increased risk of preterm labor. No published evidence was identified on FFN assessment in women with triple or higher-order gestations or in women being considered for induction. Thus, FFN assessment may be considered medically necessary in women with singleton or twin gestations who have signs or symptoms of preterm labor, since the original premise has not been disproven. However, use of FFN assessment is considered investigational for all other applications.

Practice Guidelines and Position Statements

American Congress of Obstetricians and Gynecologists

The 2016 American Congress of Obstetricians and Gynecologists (ACOG) position statement is as follows: “The positive predictive value of a positive fetal fibronectin test result or a short cervix alone is poor and should not be used exclusively to direct management in the setting of acute symptoms.”

U.S. Preventative Services Task Force

Not applicable.

KEY WORDS:

Fetal fibronectin enzyme immunoassay, fetal fibronectin, FFN, preterm labor testing, premature labor testing, cervicovaginal FFN, PTL

APPROVED BY GOVERNING BODIES:

In 1998, a rapid qualitative FFN test (Adeza Fetal Fibronectin Enzyme Immunoassay, Adeza Biomedical, Sunnyvale, CA) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process. The test is indicated:

• As an aid to rapidly assess the risk of preterm delivery in less than seven or less than 14 days from the time of sample collection in pregnant women with signs and symptoms of early preterm labor, intact amniotic membranes, and minimal cervical dilation (less than three cm) sampled between 24 weeks and less than 35 weeks’ gestation;
• For use in conjunction with other clinical information to rapidly assess the risk of preterm delivery before 35 weeks in women with singleton pregnancies undergoing a routine prenatal examination between 22 weeks and less than 31 weeks.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT codes:

REFERENCES:

1. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 171: management of preterm labor. Obstet Gynecol. 2016; 128(4):e155-e164.
2. Ben-Haroush A, Poran E, Yogev Y, Glezerman M. Vaginal fetal fibronectin evaluation before and immediately after ultrasonographic vaginal cervical length measurements in symptomatic women at risk of preterm birth: a pilot study. J Matern Fetal Neonatal Med. 2010 Aug; 23(8):854-6.
3. Berghella V, Hayes E, Visintine J et al. Fetal fibronectin for reducing the risk of preterm birth. Cochran Database Syst Rev 2008 ;(4):CD006843.
4. Berghella V, Saccone G. Fetal fibronectin testing for prevention of preterm birth in singleton pregnancies with threatened preterm labor: a systematic review and metaanalysis of randomized controlled trials. Am J Obstet Gynecol. 2016 Oct; 215(4):431-8.
5. Boots AB, Sanchez-Ramos L, Bowers DM, Kaunitz AM, Zamora J, Schlattmann P. The shortterm prediction of preterm birth: a systematic review and diagnostic metaanalysis. Am J Obstet and Gynecol. 2014; 210(1):54-e1.
6. Chan R. Biochemical markers of spontaneous preterm birth in asymptomatic women. BioMed Research International. 2014; 2014:164081.
7. Chuck AW, Thanh NX, Chari RS, Wilson RD, Janes-Kelley S, Wesenberg JC. Post-Policy Implementation Review of Rapid Fetal Fibronectin (fFN) Testing for Preterm Labour in Alberta. J Obstet Gynaecol Can. 2016; 38(7):659. Epub 2016 May 12.
8. Deshpande SN, van Asselt AD, Tomini F, Armstrong N, Allen A, Noake C, Khan K, Severens JL, Kleijnen J, Westwood ME. Rapid fetal fibronectin testing to predict preterm birth in women with symptoms of premature labour: a systematic review and cost analysis. Health Technol Assess. 2013 Sep; 17(40):1-138.
9. Esplin M, Elovitz M, Reddy U, et al. Predictive accuracy of serial transvaginal cervical lengths and quantitative vaginal fetal fibronectin levels for spontaneous preterm birth among nulliparous women. JAMA. 2017; 317(10):1047-1056.
10. Farag A, Mohammed M, Ellaithy M, Salama H.et al. Blind vaginal fetal fibronectin swab for prediction of preterm birth. Obstet Gynaecol Res. 2015; 41(7):1009-1017.
11. Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol. 2009; 113(3):585.
12. Hadźi-Lega M, Markova A, Stefanovic M, and Tantrovski M. Interleukin 6 and fetal fibronectin as a predictors of preterm delivery in symptomatic patients. Bosn Basic MedSci. 2015; 15(1):51-56.
13. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
14. Kurtzman J, Chandiramani M, Briley A et al. Quantitative fetal fibronectin screening in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Aj J Obstet Gynecol 2009; 200(3):263.e1-6.
15. McLaren JS, Hezelgrave NL, Ayubi H, Seed PT, Shennan AH. Prediction of spontaneous preterm birth using quantitative fetal fibronectin after recent sexual intercourse. Am J Obstet Gynecol. 2015 Jan; 212(1):89.e1-5. Epub 2014 Jun 30.
16. Medical Policy Reference Manual. 2.04.03 Fetal Fibronectin Enzyme Immunoassay; 2010.
17. Ruma MS, Bittner KC, Soh CB. Current Perspectives on the Use of Fetal Fibronectin Testing in Preterm Labor Diagnosis and Management. Am J Manag Care. 2017; 23:-S0.
18. Sanchez-Ramos L, Delke I, Zamora J et al. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol 2009; 114(3):631-40.
19. van Barren G-J, et al. Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor. Obstetrics & Gynecology. 2014; 123(6):1185-1193.

POLICY HISTORY:

Medical Policy Group, May 1996

Medical Policy Group, December 1996

TEC, November 1997

TEC, August 2000

Medical Policy Group, July 2002

Medical Policy Administration Committee, August 2002

Available for comment August 26-October 9, 2002

Medical Policy Group, February 2003 (2)

Medical Policy Administration Committee, March 2003

Available for comment April 1-May 16, 2003

Medical Policy Group, August 2004

Medical Policy Group, August 2006 (1)

Medical Policy Group, August 2009 (1)

Medical Policy Panel, September 2010

Medical Policy Group, October 2010 (2)

Medical Policy Administration Committee, November 2010

Available for comment November 4 - December 20, 2010

Medical Policy Group, September 2012 (3): Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group, June 2019 (9): Updates to Description, Key Points, References. Added key words: cervicovaginal FFN. No change to policy statement.

Medical Policy Group, May 2021 (9): Updates to Description, Key Points, References. Policy statement updated to remove “not medically necessary,” clarifications made to policy statement (replaced “<” with “less than”, added “amniotic” to define membranes, added “(Fetal Fibronectin Enzyme)” to define FFN) no change to policy intent. Added key word: PTL

Medical Policy Group, October 2021(9): Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, November 2022 (9): Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, May 2023 (5): Reviewed by consensus. Updates to Key Points, Benefit Application, and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, May 2024 (5): Reviewed by consensus. Updates to Key Points. No change to Policy Statement. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.